Towards a world without HIV

par Françoise Barré-Sinoussi,
janvier 2012

Despite the progress made in the field of medical research since the discovery of AIDS in 1981, it is too early to speak of a cure. In 1983 we identified the agent responsible for the progressive failure of the immune system, later naming it the human immunodeficiency virus (HIV). The last 30 years of research have provided us with profound insights into how the virus replicates itself, spreads and lies dormant in latent reservoirs within the human body. This understanding led to the revolutionary breakthrough of combination antiretroviral (ARV) therapy in 1996, which has reduced patient mortality rates by more than 85%. Not only are ARVs effective in treating HIV, they also have preventive applications. As early as 1994, the ACTG076 clinical trial showed that zidovudine (AZT) effectively prevented mother-to-child transmission of HIV. Recent studies confirm that ARVs significantly reduce the risk of the virus being sexually transmitted.

These are major developments. The fact that ARVs not only save lives, but also prevent new infections and thus check the AIDS pandemic, is a powerful argument in favour of speeding up universal access to treatment. In Botswana, where 90% of patients are under treatment, new data released by UNAIDS [1] suggests that “the number of new HIV infections … is 30% to 50% lower today than it would have been in the absence of antiretroviral therapy”.

Yet many countries cannot afford the high cost of treatment and depend heavily on international aid. Unfortunately, the global financial crisis threatens to disrupt the flow of funds, as donor countries renege on their commitments. Several recipient countries are already starting to run out of ARVs, impeding their ability to increase treatment coverage and even to secure treatments for those already treated. Even more worrying is the risk that this situation could lead to the development of newly resistant strains of HIV and produce a fresh pandemic.

We cannot allow the fight against an enemy as devastating as HIV to be undermined by politics. It is essential that innovative, durable sources of funding are found, such as the airline ticket levy used to finance the Unitaid fund. For several years now a number of voices have been calling for proceeds from a possible financial transaction tax to be channelled to health initiatives in developing countries. We must do all we can to bring this proposal to the attention of G20 leaders.

Concurrently, we must redouble our efforts to develop new therapies. Though significantly alleviated by ARVs, living with HIV remains a heavy burden. Combination ARVs must be taken for life, and they are not without side effects. They do not completely eradicate the virus : its persistence in latent reservoirs is associated with chronic generalised inflammation of the immune system. Thus patients do not recover a full life expectancy, compared with the general population, and are under increased risk of cardiovascular and neurological diseases, cancer and premature ageing.

Eradicating HIV will long remain a dream. Even so, some models lead us to believe part of the dream could eventually come true if we succeed in developing new shortterm therapeutic strategies, which may result in life-long remission without the need for drug therapy.

The recent case of Timothy Ray Brown, known as the “Berlin patient”, suggests such strategies may one day become feasible. Brown had been living with HIV for over ten years when, in his early forties, he underwent a bone marrow transplant to treat leukaemia. His doctor searched for a compatible donor with a particular genetic characteristic : a mutation of the CCR5 co-receptor, a molecule which acts as a “docking station” on the surface of CD4+ T cells (the cells specifically targeted by HIV), through which the virus enters the cell. It has been known for some years that those (of Caucasian origin) who exhibit this rare genetic mutation, known as Delta32, are in fact protected from HIV infection.

Brown ended his ARV treatment on the day of his bone marrow transplant. Five years on, the most sophisticated tests reveal no trace of HIV in any of the compartments in which the virus establishes reservoirs throughout the body, such as the gut or central nervous system. Yet Brown’s immune system continues to produce antibodies, indicating the infection may not have completely vanished. It is difficult to confirm scientifically that the Delta32 mutation alone is responsible for this “cure”. Many other therapeutic elements may have contributed to the outcome of what was a very complex operation. Although such a costly and risky procedure cannot be implemented on a large scale, it opens the door to gene therapy focused on CCR5 receptors, among other targets.

Patients called HIV controllers represent the ideal model for longterm remission. They are rare individuals (only 0.3% of those infected) who have been HIV positive for at least 10 years and maintain undetectable viral load without ARV treatment, and show no sign of progressing to AIDS. Strikingly, these patients exhibit a smaller viral reservoir compared with other patients. We now know that this extremely powerful natural control of the infection is regulated by two mechanisms. The first activates cytotoxic T cells, which kill virally infected cells, while the second is linked to the immune cells’ intrinsic resistance. Understanding these processes can help us develop new therapies, perhaps one day enabling all those living with HIV to suppress viral replication without ARV treatment.

A unique study in France, named Visconti, has assembled 18 patients who were tested within two to three months after HIV infection and immediately placed on ARV. Some years later, with their doctors’ consent, they ended their ARV treatment and have since kept their infections in check. The study confirms the benefits of treating HIV at the very early stages of infection. There is an immensely valuable store of knowledge to be gained from analysing the immunological characteristics that made therapy redundant for these patients.

As the natural carriers of the simian immunodeficiency virus (SIV), from which HIV originated, African monkeys present a final object of study. Unlike HIV in humans, SIV-infected monkeys do not go on to develop AIDS ; any immune reaction to the virus is quickly subdued. As a result, the virus multiplies freely among monkeys, without provoking the deleterious chronic inflammation observed in human infection.

The mechanisms we must induce in order to trigger a protective response against HIV/AIDS remain a mystery. A combination of vaccines and therapeutic approaches will most likely prove necessary. This is the focus of a working group formed under the auspices of the International Aids Society (IAS), composed of international scientists aiming to develop a global scientific strategy to deal with HIV persistence, in the hope that we will one day live in a world without AIDS.

Research surrounding HIV/AIDS has useful implications beyond the epidemic itself. HIV is a tool that helps us to better understand the specific mechanisms at the heart of our immune systems. There is also much to be learned from research in cancer and other chronic pathologies linked to inflammatory abnormalities. In this time of crisis, we are faced with two choices : either we work in collaboration in a spirit of solidarity, as we did at the beginning of this epidemic, or we adopt an “every man for himself” approach, to the detriment of us all.

P.-S.

Translated by Wolf Draeger

Françoise Barré-Sinoussi is a researcher at the Institut National de la Santé et de la Recherché Médicale (Inserm) and the Institut Pasteur. She was awarded the Nobel Prize in Medicine in 2008